Abstract
Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduces peritoneal macrophage populations and increases the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM are replaced by monocyte-derived LpM decreases the number of lesions that develop. We propose a putative model whereby endometrial macrophages are "proendometriosis" while newly recruited monocyte-derived macrophages, possibly in LpM form, are "antiendometriosis." These observations highlight the importance of monocyte-derived macrophages in limiting disease progression.
Highlights
Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue outside the uterus
We investigated infiltration of large peritoneal macrophages (LpM) into endometriosis lesions using dual immunodetection for F4/80 and the transcription factor GATA binding protein 6 (GATA6; LpM marker, green; Fig. 1C)
We performed adoptive transfer of GFP+ LpM isolated by fluorescent activated cell sorting (FACS) from MacGreen mice (LpM and SpM were determined based on expression of F4/80 and major histocompatibility class II (MHCII), discussed below)
Summary
Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. Macrophages are exceptionally diverse cells present in all tissues of the body that perform functions vital for immunity, development, tissue homeostasis, and repair following injury They modify their role depending on signals received from their local microenvironment and exhibit high degrees of transcriptional and phenotypic heterogeneity and tissue-specific function [1, 2]. During acute liver injury hepatic resident macrophages (Kupffer cells) become activated and recruit monocytes that initially promote liver injury but subsequently differentiate into inflammatory macrophages and help resolve injury and drive regeneration [7] In pancreatic cancer, both tissue-resident and monocyte-derived macrophages populate the tumor and increase in density as the cancer progresses. C.B.C. is a guest editor invited by the Editorial Board
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